Diabetes Mellitus is a common and serious chronic disease, which afflicts about 177 million people worldwide, 17 million people in the United States and is the fourth leading cause of death. It leads to long-term complications such as coronary artery disease, hypertension, retinopathy, neuropathy and nephropathy. Research indicates that self-monitoring of blood glucose levels prevents or slows down the development of these long term complications. An optical polarimetric glucose sensor provides a means for the noninvasive measurement of glucose concentration, thereby reducing pain and complications associated with the current invasive methods.
The use of polarimetry in the detection of analyte concentration has existed for several years. Pohjola demonstrated that glucose concentration in the aqueous humor of the eye is correlated to that of blood. In 1982 March et al. were the first to propose the use of polarimetry to indirectly estimate blood glucose levels via the aqueous humor of the eye. They found in order to measure millidegree sensitive rotations due to glucose at physiological levels a very sensitive and stable polarimeter is required. In the past decade considerable work has been done in the development of such a polarimeter. Coté et al. reported on the potential of millidegree sensitivity by utilizing a true phase technique. This work was later followed by Cameron et al. who reported on a Faraday based polarimeter using a digital closed-loop feedback technique with sub-millidegree sensitivity. Since then, different polarimetric variations have been illustrated by several groups to measure glucose concentration. Chou et al. reported on a polarimeter utilizing an optical heterodyne approach with the ability to detect glucose levels below 10 mg/dl; however, the open loop system lacked stability due to fluctuations in the laser intensity and noise. Most recently, Ansari et al. proposed a theoretical model using the Brewster's reflection off the eye lens for measuring glucose concentration.
Though aqueous humor of the eye contains glucose, it also has other optically active components that can contribute to the overall optical rotation. To estimate glucose concentration in the presence of other optically active components, King et al. demonstrated the use of a multi-spectral Pockels cell based system. This work was followed by Cameron et al. who used a multi-spectral Faraday-based system which also demonstrated the potential to overcome rotations due to the presence of other optically active components. Though glucose concentration in the aqueous humor correlates to that of blood, there is a transport time delay between the diffusion of glucose from the blood into the aqueous humor. If such measurements are to be of benefit to a diabetic person as a reliable predictor of blood glucose concentration, the time delay should be below 10 minutes. In 2001, Cameron et al. measured the transport time delay in a rabbit model and had shown this delay to be under the 10 minute threshold. Most recently, Baba et al. have shown the effects of temperature and pH to be negligible in the normal physiological range.
The main problem currently hindering the development of a viable polarimetric system to indirectly measure blood glucose levels in the aqueous humor of the eye is the birefringence of the cornea associated with motion artifact. Since the birefringence of the cornea is spatially varying, as the cornea moves with respect to the sensing light beam, this motion induced time varying birefringence tends to mask the detected glucose signal.
To date, time varying corneal birefringence due to motion artifact is the main factor limiting in vivo polarimetric glucose measurements in the eye which is not addressed by current glucose sensing polarimeters. U.S. Pat. No. 5,303,709 disclosed a system to facilitate diagnosis of retinal eye disease. To minimize effects of corneal birefringence, this system utilized a backscattered beam from the retina coupled to a variable retarder to reduce corneal birefringence contributions on nerve fiber retinal layer measurements. The compensation implementation in the '709 patent incorporated a polarization sensitive confocal system integrated into a scanning laser retinal polarimeter. U.S. Pat. No. 6,704,106 disclosed a method and system to cancel retardance error in regards to retinal nerve fiber layer measurements. To achieve this, four retardance measurements collected over one complete rotation of a mechanically rotated half-wave retarder are averaged to minimize effects of system birefringence, leaving a mean retardance measurementfree of residual polarization bias. In U.S. Pat. No. 6,356,036, a system and method for determining birefringence on the anterior segment (i.e. cornea and lens) of a patient's eye was disclosed. This method involved using a backscattered (i.e. reflected) light beam similar to that disclosed in '709 except the patient's lens reflection intensity through confocal imaging is no longer used as a reference and birefringence of all segments of the eye that are anterior to the retina are determined using a direct polarization beam. In other words, '036 eliminated the need for a confocal imaging system and the scanning laser polarimeter was now able to use the same path to measure birefringence of the anterior segment of the eye. In regards to the invention disclosed herein, a propagated polarized laser beam, not backscattered, passes directly through the anterior chamber of the eye and does not interact with the lens or retina. In addition, the compensator is tied to an autonomous controller system to compensate for corneal birefringence effects in real-time.
Accordingly, it is an object of the present invention to provide an improved noninvasive glucose sensing polarimeter that incorporates a new method to overcome the effects of corneal birefringence, therefore, allowing for the realization of in vivo polarimetric glucose measurements. In addition, such an implementation as described herein would allow for the detection of any optically active molecule in a medium or sample in which birefringence is a problem. Furthermore, the approach to birefringence compensation could be implemented in most types of optical polarimeters, other than the Faraday approach as described herein.
The prior art fails to provide any practical, workable polarimeter system which can consistently provide accurate measurements of the glucose level in human tissue. There is a strong but unmet need for a practical, reliable system which overcomes the problems of the prior art to provide a noninvasive system for measurement of human glucose levels.
Some prior art systems are not noninvasive and certain polarimetric based systems, used for analyte sensing, are not birefringence compensated. The systems do not employ a birefringence compensator, nor do they sense real-time corneal birefringence. The ability to sense and compensate for birefringence effects allows for analyte measurements regardless of light path (i.e. location).